Human testicular insulin-like factor 3: in relation to development, reproductive hormones and andrological disorders

Abstract

Knockout of the gene encoding insulin-like factor 3 (INSL3) results in cryptorchidism in mice due to disruption of the transabdominal phase of testicular descent. This finding was essential for understanding the complete course of testis descensus, and wound up years of speculations regarding the endocrine regulation of this process. INSL3 is, along with testosterone, a major secretory product of testicular Leydig cells. In addition to its crucial function in testicular descent, INSL3 is suggested to play a paracrine role in germ cell survival and an endocrine role in bone metabolism. INSL3 is produced in human prenatal and neonatal, and in adult Leydig cells to various extents, and is in a developmental context regulated like testosterone, with production during second trimester, an early postnatal peak and increasing secretion during puberty, resulting in high adult serum levels. INSL3 production is entirely dependent on the state of Leydig cell differentiation, and is stimulated by the long-term trophic effects mediated by luteinizing hormone (LH). Once differentiated, Leydig cells apparently express INSL3 in a constitutive manner, and the hormone is thereby insensitive to the acute, steroidogenic effects of LH, which for example is an important factor in the regulation of testosterone. Clinically, serum INSL3 levels can turn out to be a usable tool to monitor basal Leydig cell function in patients with various disorders affecting Leydig cell function. According to animal studies, foetal INSL3 production is, directly or indirectly, sensitive to oestrogenic or anti-androgenic compounds. This provides important insight into the mechanism by which maternal exposure to endocrine disrupters can result in cryptorchidism in the next generation. Conclusively, INSL3 is an interesting testicular hormone with potential clinical value as a marker for Leydig cell function. It should be considered on a par with testosterone in the evaluation of testicular function and the consequences of Leydig cell dysfunction.

Importance of Serum Testicular Protein Hormone Measurement in the Assessment of Disorders of Sex Development

“…1 ). They are high until the 3rd-6th month and then decline to very low levels until the onset of puberty, when they increase again, following the LH pattern [Bay and Andersson, 2011]. The main difference between testosterone and INSL3 as Leydig cell markers is that INSL3 does not respond acutely to an LH or hCG stimulus.…”

Transabdominal Migration of the Testis

“…Similar to testosterone, INSL3 production is responsive to trophic stimulation by luteinising hormone (LH), but its production is less sensitive to LH levels than testosterone [ 32 ]. Acting through its receptor in the gubernaculum, relaxin family peptide receptor 2 (RXFP2), INSL3 stimulates the swelling reaction in the gubernaculum [ 33 , 34 ].…”

A hormonális rendszer válsága: az endokrin diszruptorok egészségügyi hatásai

“…Az erectilis diszfunkció a műanyag-iparban dolgozó férfiak esetében hétszer gyakoribb volt, mint az átlagpopulációban, miközben csökkent a libidó és általában a szexuális élettel való elégedettség [31,32]. Állatkísérletekben éppúgy, mint emberben, a DES és pesticidek növelik a cryptorchidismus előfordulását [33][34][35]. Mindez együttesen növeli az infertilitást.…”